A Neo-substrate That Amplifies Catalytic Activity of Parkinson's-disease-related Kinase PINK1

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Aug 20

PMID 23953109

Citations 136

Authors

Nicholas T Hertz

Amandine Berthet

Martin L Sos

Kurt S Thorn

Al L Burlingame

Ken Nakamura

Kevan M Shokat

Affiliations

Soon will be listed here.

Abstract

Mitochondria have long been implicated in the pathogenesis of Parkinson's disease (PD). Mutations in the mitochondrial kinase PINK1 that reduce kinase activity are associated with mitochondrial defects and result in an autosomal-recessive form of early-onset PD. Therapeutic approaches for enhancing the activity of PINK1 have not been considered because no allosteric regulatory sites for PINK1 are known. Here, we show that an alternative strategy, a neo-substrate approach involving the ATP analog kinetin triphosphate (KTP), can be used to increase the activity of both PD-related mutant PINK1(G309D) and PINK1(WT). Moreover, we show that application of the KTP precursor kinetin to cells results in biologically significant increases in PINK1 activity, manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Discovery of neo-substrates for kinases could provide a heretofore-unappreciated modality for regulating kinase activity.

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